Neuronal populations in the inferior temporal gyrus with truncated tau inclusions occur as early as those with hyperphosphorylated tau inclusions in Alzheimer’s disease, however they do not completely overlap

Abstract

AbstractBackgroundAlzheimer’s disease (AD) features stereotypical spread of hyperphosphorylated tau (p‐tau) and beta‐amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always overlap with p‐tau, making the latter an excellent marker of tau pathology burden. We recently showed in experimental studies that truncated tau (tr‐tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p‐tau in neurons at late AD stages; however, only about 40% of tr‐tau positive neurons also show p‐tau positivity. This makes tr‐tau a potential marker of AD previously invisible at neuropathological investigation or a potential target of diagnostic tool development. We sought to determine how early in AD tr‐tau is detected compared to p‐tau and to what degree tr‐tau and p‐tau neuronal populations overlap at early AD stages.MethodsWe used multiplex immunofluorescence to probe tr‐tau (D13, D402, D418, TauC3) and p‐tau (PHF1) species in the same tissue slides of postmortem human brain tissue of healthy controls and subjects at progressive AD stages. We quantified neuronal tau pathology and colocalization in digital images of inferior temporal gyrus (ITG) as representative of an area involved in p‐tau pathology in intermediate stages.ResultsOur preliminary analysis included 14 cases (4 controls, 10 AD) from all Braak stages (1:1:2:3:3:2:2 for Braak 0 through 6). Of the cases used in the study, 71% were male and the mean (SD) age of death was 82.3 (10.9). As expected, p‐tau was detected from Braak 4; however, we detected tr‐tau species from Braak 3 (Fig. 1). Both p‐tau and tr‐tau burden increased with Braak stage (Fig. 2). The overlap between tr‐tau and p‐tau positive neuron populations was 30.8% at Braak 4 (Fig. 3A) and increased to 54.6% at Braak 6 (Fig. 3B).ConclusionNeuronal tr‐tau deposits develop in AD as early as p‐tau pathology. Even in earlier stages, the % of overlapping is moderate. This corroborates tr‐tau as a potential biomarker of tau pathology in AD not covered by p‐tau screening. We are currently finalizing analysis of a much larger cohort including other brain regions.